Sucralose is an artificial sweetener and activates the glucose-sensing receptor expressed in pancreatic β-cells. Although sucralose does not enter β-cells nor acts as a substrate for glucokinase, it induces a marked elevation of intracellular ATP ([ATP]
c). The present study was conducted to identify the signaling pathway responsible for the elevation of [ATP]
c induced by sucralose. Previous studies have shown that sucralose elevates cyclic AMP (cAMP), activates phospholipase C (PLC) and stimulates Ca
2+ entry by a Na
+-dependent mechanism in MIN6 cells. The addition of forskolin induced a marked elevation of cAMP, whereas it did not affect [ATP]
c. Carbachol, an activator of PLC, did not increase [ATP]
c. In addition, activation of protein kinase C by dioctanoylglycerol did not affect [ATP]
c. In contrast, nifedipine, an inhibitor of the voltage-dependent Ca
2+ channel, significantly reduced [ATP]
c response to sucralose. Removal of extracellular Na
+ nearly completely blocked sucralose-induced elevation of [ATP]
c. Stimulation of Na
+ entry by adding a Na
+ ionophore monensin elevated [ATP]
c. The monensin-induced elevation of [ATP]
c was only partially inhibited by nifedipine and loading of BAPTA, both of which completely abolished elevation of [Ca
2+]
c. These results suggest that Na
+ entry is critical for the sucralose-induced elevation of [ATP]
c. Both calcium-dependent and -independent mechanisms are involved in the action of sucralose.
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